According to the Oxford team, which published its study (“8.2% of the Human Genome Is Constrained: Variation in Rates of Turnover across Functional Element Classes in the Human Lineage”) in PLOS Genetics, the 80% claim has been controversial, with many in the field arguing that the biochemical definition of 'function' was too broad—that just because an activity on DNA occurs, it does not necessarily have a consequence. For functionality you need to demonstrate that an activity matters.

To reach their figure, the Oxford University group took advantage of the ability of evolution to discern which activities matter and which do not. They identified how much of our genome has avoided accumulating changes over 100 million years of mammalian evolution—a clear indication that this DNA matters; it has some important function that needs to be retained.

“Constrained DNase 1 hypersensitivity sites, promoters, and untranslated regions have been more evolutionarily stable than long noncoding RNA loci, which have turned over especially rapidly,” wrote the investigators. “By contrast, protein coding sequence has been highly stable, with an estimated half-life of over a billion years (d1/2 = 2.1–5.0). From extrapolations we estimate that 8.2% (7.1–9.2%) of the human genome is presently subject to negative selection and thus is likely to be functional, while only 2.2% has maintained constraint in both human and mouse since these species diverged. These results reveal that the evolutionary history of the human genome has been highly dynamic, particularly for its noncoding yet biologically functional fraction.”

“This is in large part a matter of different definitions of what is 'functional' DNA,” says joint senior author Chris Pointing, Ph.D., of the MRC Functional Genomics Unit at Oxford University. “We don't think our figure is actually too different from what you would get looking at ENCODE's bank of data using the same definition for functional DNA.”

“But this isn't just an academic argument about the nebulous word function. These definitions matter. When sequencing the genomes of patients, if our DNA was largely functional, we'd need to pay attention to every mutation. In contrast, with only 8% being functional, we have to work out the 8% of the mutations detected that might be important. From a medical point of view, this is essential to interpreting the role of human genetic variation in disease.”

The researchers used a computational approach to compare the complete DNA sequences of various mammals, from mice, guinea pigs, and rabbits to dogs, horses, and humans. Gerton Lunter, Ph.D., from the Wellcome Trust Centre for Human Genetics at Oxford University, the other joint senior author, explained: “Throughout the evolution of these species from their common ancestors, mutations arise in the DNA and natural selection counteracts these changes to keep useful DNA sequences intact.”

The rest of the human genome, the non-8.2%, is leftover evolutionary material, parts of the genome that have undergone losses or gains in the DNA code, often called “junk” DNA.

Readers' Comments

Posted 07/26/2014 by renas Isa

Well, rather than 'Hub-DNA' from now on, it should be called 'Fictional-DNA'.

Posted 07/25/2014 by Mike Brody

This “debate” has been going on for a long time, and quite frankly has been fueled by generalizations, limited data sets, and funding prejudice. The talking heads that have framed this nonissue, often mock those researchers who ask “why is only a portion of the genome being used”? The 8.2% assertion is akin to the morons who asserted that humans only use 10% of their brain, again a nonissue, and one wonders who other than Hollywood benefits from such trivial pursuits. The latest bunch of molecular strict constructionists are reframing what their definition of “is” is: Is it functional by their definition of what is functional? Who cares? Their disingenuousness averts a growing list of accepted functions such as chromosomal inactivation, specific gene regulations, developmental initiations, epigenetic control of gene expressions, facilitations of neoplastic progression, etc. by hundreds of non-coding RNAs, which may someday at the present rate of discovery, reach into the thousands. I would like the editors and reporters to consider asking the Luddites, flat earthers, or climate change deniers who wish to continue to keep us ignorant, a reasoned inquiry about their assumptions and how they account for “data” which is inconsistent with their assertions.

Posted 07/25/2014 by Misaki WAYENGERA

So now we have two scientists presenting differing data in context of the same terminology (functional) and yet their message is clearly differing. I would call this stable DNA, "Hub-DNA" rather than functional DNA. The authors of this work have failed to apply existing nomenclature (at protein level) to define the basic principle underlying their findings. In protein science, talking from protein-protein-interaction networks, those proteins that remain stable over evolutionary time; are denoted "hub" proteins; not functional. Theoretically, it is plausible that their cDNA is equally constrained; and thereby conserved over time. Big data science should strive to use the same language, to avoid confusion.

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